Cancer, also known as malignant tumor, is a common disease that seriously threatens human health. At present, the mortality rate of cancer is still rising, but there still lacks of effective drugs treating common solid tumors.
Cells acquire the ability of unlimited proliferation due to the activation of the oncogenes, which is the main reason for carcinogenesis. It has been proved that the inhibition of the cell apoptosis pathways, which are under strict genetic and biochemical regulations, is another important reason for carcinogenesis. Through membrane blebbing, the apoptotic cells formed apoptotic bodies that are coated by cell membrane, and those apoptotic bodies are quickly cleared by phagocytes. As a result, inducing apoptosis in tumor cells can have anticancer effects without strong immune response, therefore inducing apoptosis in tumor cells has become more important in cancer treatment. In recent years, with the development of research on the mechanism of cell apoptosis, depletion of reduced glutathione (GSH) has been found in the process of inducing apoptosis of tumor cells. The level of GSH is closely related to cell apoptosis, and synthetic inhibitors and GSH conjugant have anticancer function via inducing apoptosis of tumor cells. The latest study has shown that the level of GSH in cells determines the effect of the apoptosis of human M14 melanoma cells induced by c-myc oncogene, further proving GSH plays an important role in the process of cell apoptosis.
Intracellular GSH level is relevant to cell proliferation rate. Growth rate limited tumor cells have a significantly increased demand for GSH, and the GSH levels are elevated in various human cancer tissues such as pancreas, lung, ovary, larynx, breast and liver cancer tissues compared with normal tissues in these regions. For example, the total GSH content is (17.5±2.3) nmol/mg protein in pancreatic tumor tissue, while the content is (8.8±1.4) nmol/mg in normal pancreatic tissue, P<0.004; The GSH content in liver tumor tissue is twice more than that in normal tissue, wherein the total GSH content in former is (41.9±7.2) nmol/mg protein and that in latter is (22.4±3.5) nmol, P<0.02. Although the level of GSH in tumor tissues is significantly higher than that in normal tissues, it can only meet the needs of tumor growth and proliferation. On the other hand, the level of GSH in normal cells is much higher than that needed by normal metabolism. As such, tumor cells have a much higher sensitivity to GSH depletion than normal cells. It has been reported that in 18 human neuroblastoma cell lines, when intracellular GSH levels are decreased by 90%, then these cells are subjected to apoptosis, while the function of normal cells under the same conditions is almost not affected. Therefore, it is possible to selectively induce apoptosis in tumor cells through GSH depletion.
With the advance of study on molecular biological mechanism of apoptosis, inducing apoptosis in tumor cells provides a new idea and a new pathway for tumor chemical therapy. Many apoptosis inducing agents of tumor cells are related with GSH depletion. It is also believed that intracellular GSH depletion is the common mechanism of inducing tumor cell apoptosis by various factors. Compared with the GSH level in normal cells, tumor cells contain a higher level of GSH and have a bigger demand for GSH. Therefore, theoretically, synthetic inhibitors and conjugant of GSH can selectively induce apoptosis in tumor cells when used alone, and they can reverse the multi-drug resistance of tumor cells when used in combination with other anticancer drugs, thus increase the sensitivity of tumor cells to chemotherapeutic drugs, and bring new prospect to improve the ability of the selectivity and targeting of cancer chemotherapy.